The investigator proposes to fine-map and positionally clone quantitative trait loci (QTLs) responsible for variation in body size and obesity in the cross of LG/J by SM/J inbred mouse strains. The use of animal models for mapping obesity-related genes has several advantages relative to working in human populations. Principally, powerful, replicable experimental designs are available for gene mapping and validation. Under previous support, 11 QTLs for body size in a replicate F2 intercross population have been confirmed and it has been determined which of these QTLs affects adiposity levels. The investigator is narrowing QTL support intervals in the F10 generation of an Advanced Intercross (AI) line from 20 cM to less than 5 cM. Under the present proposal, the QTL support intervals will be further limited to approximately 1 cM by saturation mapping in the F7 and F10 AI line generations, by performing Recombinant Inbred Segregation Tests and forming congenic strains. In addition, previously cloned candidate genes will be sequenced to determine whether they show molecular polymorphism between the LG/J and SM/J strains. Once support intervals reach the 1 cM level, positional cloning will be performed using bacterial artificial chromosomes (BACs). When a compelling candidate gene is identified by database searches or positional cloning, it will be tested using the quantitative hybrid complementation test. In addition to positional cloning of the QTLs, congenic strains will be formed for each QTL and will be tested, along with the LGxSM recombinant inbred strains for a variety of obesity-related traits.